在SARS-CoV-2 nsp16中发现一种可用药物的神秘口袋,使用菌抑制剂
Nicole L Inniss1, Ján Kozic2, Fengling Li3
1Department of Microbiology-Immunology and Center for Structural Biology of Infectious Diseases, Northwestern University, Feinberg School of Medicine, Chicago, Illinois 60611, United States.
ACS infectious diseases
|September 20, 2023
概括
研究人员发现了一种新的小分子抑制剂 (化合物5a),向SARS-CoV-2 nsp16酶. 这种化合物与独特的口袋结合,为开发泛冠状病毒疗法提供了新的策略.
科学领域:
- 病毒学 病毒学
- 药用化学 医学化学
- 结构生物学 结构生物学
背景情况:
- SARS-CoV-2 nsp16-nsp10 2'-O-甲基转移酶对于病毒RNA封闭至关重要.
- 开发新型抑制剂是打击SARS-CoV-2和其他冠状病毒的关键.
研究的目的:
- 为了发现SARS-CoV-2 nsp16.16的新型小分子抑制剂.
- 研究已识别的抑制剂的结合机制和治疗潜力.
主要方法:
- 高通量查 (HTS) 用于识别抑制剂.
- 用X射线晶体学来确定结合模式.
- 基于细胞的测试来评估抗病毒活性和细胞毒性.
主要成果:
- 化合物5a被确定为SARS-CoV-2 nsp16.2的抑制剂.
- X射线结构揭示了5a与SAM结合部位附近的一个神秘口袋的共价结合.
- 5a衍生物抑制了nsp16活性和小鼠肝炎病毒复制,但显示出细胞毒性.
结论:
- 新发现的nsp16密码口袋是可以使用的.
- 化合物5a及其衍生物作为有价值的工具化合物.
- 结构引导设计为针对nsp16.16的泛冠状病毒疗法提供了一个有希望的方法.
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